MN-166 (ibudilast) is an investigational therapy being developed by MediciNova to treat amyotrophic lateral sclerosis (ALS), progressive multiple sclerosis, and drug dependence. MediciNova has also marketed the drug in Japan and South Korea since 1989 to treat post-stroke complications and bronchial asthma.

How MN-166 works

MN-166 is a small molecule that inhibits the action of enzymes called phosphodiesterase (PDE) -4 and -10 and that of macrophage migration inhibitory factor (MIF), which all play important roles in inflammation. MN-166 also blocks the activity of cell signaling molecules that play a role in inflammation, promoting the survival, development, and function of nerve cells. Finally, it attenuates activated glial cells, which play a major role in certain neurological conditions.

The anti-inflammatory and neuroprotective effects of MN-166 have been shown in preclinical and clinical studies.

MN-166 in clinical trials

A randomized, double-blind, placebo-controlled, Phase 2 clinical trial (NCT02238626) evaluated the safety, tolerability, and clinical responsiveness of 60 mg of MN-166 per day administered as an adjunct or add-on therapy to 100 mg of Rilutek (riluzole) per day.

The study consisted of two treatment arms, MN-166 and placebo. Participants were first screened for up to three months, followed by a six-month double-blind phase in which neither patients nor clinicians knew who was getting MN-166 and who was getting a placebo. Those on placebo were then treated with open-label MN-166 for six months. The follow-up phase began two weeks after the last dose.

During the treatment phase, participants returned to the clinic at months 3 and 6 and were telephoned at months 1, 2, 4, and 5 to collect information about side effects and any other drugs they might have been taking.

Researchers assessed the safety of MN-166 by monitoring and recording all serious adverse events and discontinuations as a result of the treatment. Additional assessments included the monitoring of blood and urine values, vital signs, electrocardiograms (ECG), medical history, and physical and neurological examinations.

Data from 51 patients without non-invasive ventilation (NIV) showed that treatment with MN-166 is safe and well-tolerated, achieving the study’s primary endpoint, and more effective in improving patients’ function than placebo.

Seven serious adverse events were reported, but none was related to the treatment. All adverse events related to treatment were mild to moderate, the most common being loss of appetite, nausea, and anorexia.

More patients taking MN-166 responded to treatment as measured by the ALS functional rating scale-revised (ALSFRS-R), which looks at the functional activity of ALS patients, than those on placebo in the first six months (29.4 percent versus 17.6 percent). Additionally, 35.3 percent of patients who switched from placebo to MN-166 in the six-month extension period responded when given MN-166.

As the disease progresses, patients usually have lower scores on the ALSFRS-R score. A responder was defined as a patient who had improved, had no change, or declined by one point on the scale. A non-responder was defined as a patient who declined by two points or more on the scale.

More patients taking MN-166 than patients taking placebo also responded to treatment as measured by the ALS assessment questionnaire (ALSAQ-5) during the first six months of the study (50 percent versus 23.5 percent). Similarly, 29.4 percent of patients who switched from placebo to MN-166 in the six-month extension period responded to MN-166.

ALSAQ-5 measures the physical mobility, activities of daily living and independence, eating and drinking, communication, and emotional functioning of ALS patients. A responder was defined as a patient whose score improved or did not change, and a non-responder as a patient whose score declined.

An additional analysis that did not only include data from patients without NIV but also those with NIV also showed that treatment with MN-166 improves ALSAQ-5 and ALSFRS-R scores.

In another open-label Phase 1/2 clinical trial (NCT02714036), 35 participants received 100 mg of MN-166 per day for 36 weeks. A primary measured outcome was the impact of MN-166 on markers of inflammation. The results of this study have not been published yet, but based on a discussion of the results with the U.S. Food and Drug Administration (FDA), MediciNova now plans a Phase 2b/3 clinical trial to further test the efficacy and safety of MN-166 for ALS.

Approximately 150 ALS patients will be randomized to receive either 100 mg of MN-166 per day or a placebo for nine months. The primary endpoint will be the change in functional activity, measured by the ALSFRS-R score. Secondary endpoints will include changes in muscle strength, quality of life, use of NIV, safety, and tolerability.

The company hopes that the results from this trial will support the submission of a new drug application (NDA), which is a prerequisite for the approval of MN-166 as a treatment for ALS.

Additional information

The FDA granted MN-166 fast-track status in December 2015 and designated it an orphan drug in October 2016.

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